Efavirenz is an active pharmaceutical ingredient used in the manufacture of medicaments for the treatment and prevention of HIV/AIDS. Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. It is generally recommended for use with other antiretrovirals, for example in combination with Emtricitabine, Lamivudine, and/or Tenofovir. Efavirenz is listed on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.
There are numerous processes and synthetic routes described in the prior art for the preparation of Efavirenz. However, existing synthesis methodologies for the production of these compounds have essentially been based on standard stirred batch or bench top reactor type processes which utilize significant volumes of organic solvents. These processes have its limits, including inefficient temperature and pressure controls as well as the inability to handle hazardous reagents safely. The application of continuous flow microreactors, or micro reactor technology, to reaction chemistries such as this one, could provide a potential practical solution that could be used to overcome some of these drawbacks.
In addition, Efavirenz has a stereogenic quaternary carbon center bearing a trifluoromethyl group with the (S) configuration. Biological evaluation of optically active Efavirenz has revealed that the (R) enantiomer exhibits virtually no activity. Therefore, establishment of the quaternary carbon center with the (S) configuration in an asymmetric manner is one of the main challenges for the synthesis of Efavirenz.
Correia et al., Angew. Chem. Int. Ed. 2015, 54, 4945-4948 discloses a method for the flow synthesis preparation of Efavirenz. The disclosure relates to a five step process for the synthesis of a racemic mixture of Efavirenz with an overall yield of 45% rac-Efavirenz.
There is therefore a need for an improved method for the manufacture of Efavirenz. In particular, there is a need for a method for the manufacture of the (S) enantiomer of Efavirenz, the method preferably being a flow synthesis method. The present invention seeks to address some of the shortcomings of the prior art by providing new methods for the manufacture of optically pure Efavirenz.